Effervescent drug delivery system for oral administration

ABSTRACT

The pharmaceutical compositions of the present invention comprise orally administerable dosage forms that use effervescence as a penetration enhancer for drugs known, or suspected, of having poor bioavailability. Effervescence can occur in the stomach, once the tablet or other dosage form is ingested. In addition to effervescence in the stomach, or as alternative technique, by the use of appropriate coatings and other techniques, the effervescence can occur in other parts of the gastrointestinal tract, including, but not limited to, the esophagus, duodenum, and colon. The site of effervescence and drug release is chosen to correspond with the segment of the gastrointestinal tract displaying maximal absorption of the formulated drug, or to gain some other therapeutic advantage.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 09/302,105, filed Apr. 29, 1999, which in turn claims the benefit ofU.S. Provisional Patent Application No. 60/083,391, filed Apr. 29, 1998,the disclosure of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Many orally-administered drugs display poor bioavailability whenadministered in conventional dosage forms, i.e., the rate and extent towhich the drugs are absorbed is less than desirable. With several drugs,absorption may be as little as 30% or less of the orally administereddose. To compensate for this effect, a very large dose is oftenadministered so that absorption of the therapeutically required quantityof the drug can occur. This technique may prove costly with expensivedrugs; and the nonabsorbed drug may also have undesirable side effectswithin the gastrointestinal tract. In addition, poorly absorbed drugsoften display large inter- and intrasubject variability inbioavailability. See Aungst, B. J., J. Pharm. Sci., 82:979-87, 1993.Specific examples (with the average bioavailability given inparentheses) include methyldopa (25%) with a range of 8% to 62%. SeeKwan, K. C., Folz, E. L., Breault, G. O., Baer, J. E., Totaro, J. A., J.Pharmacol. Exp. Ther., 198:264-77, 1976; and nalbuphine (approximately17%) with a range of 6% to 40%. See Lo, M.-W, Schary, W. L., Whitney, C.C., Jr., J. Clin. Pharmacol., 27:866-73, 1987. Such variation in theamount of drug absorbed does not allow for good control of the diseasecondition.

To improve the bioavailability of poorly absorbed drugs, penetrationenhancers have also been employed. However, many of the penetrationenhancers referred to in the current literature damage the absorbingtissues and thus are not a practical solution to the problem of poorbioavailability. In fact, it has been suggested that the damage to themucosa caused by these agents may be the factor responsible for theimproved absorption. See LeCluyse, E. L. and Sutton, S.C., Advanced DrugDelivery Reviews, 23:163-83, 1997.

Other techniques which have been employed to improve bioavailabilityinclude using enteric coated tablets having effervescence to rapidlydissolve or disperse the dosage form in the stomach. See U.S. Pat. Nos.4,503,031; 4,289,751; and 3,961,041.

SUMMARY OF THE INVENTION

The pharmaceutical compositions of the present invention comprise orallyadministerable dosage forms that use effervescence as a penetrationenhancer for drugs known, or suspected, of having poor bioavailability.Effervescence can occur in the stomach, once the tablet or other dosageform is ingested. In addition to effervescence in the stomach, or asalternative technique, by the use of appropriate coatings and othertechniques, the effervescence can occur in other parts of thegastrointestinal tract, including, but not limited to, the esophagus,duodenum, intestinal and colon. The site of effervescence and drugrelease is chosen to correspond with the segment of the gastrointestinaltract displaying maximal absorption of the formulated drug, or to gainsome other therapeutic advantage. Desirably, such site is not in themouth of the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. is an enlarged top plan view of a tablet which has a bioconcavedshaped.

FIG. 2. is an enlarged side view of an enteric coated multilayeredtablet.

FIG. 3. is an enlarged top view of an enteric coated multilayeredtablet, which depicts the effervescent external to the mucous adhesivelayer.

FIG. 4. is an enlarged top view of an enteric coated multilayeredpellet, which depicts the effervescent external to the mucous adhesivelayer.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The pharmaceutical compositions of the present invention comprise orallyadministerable medicaments in combination with an effervescent as apenetration enhancer for influencing absorption of a drug in thegastrointestinal tract. Effervescence leads to an increase in the rateand/or the extent of absorption of the drugs that are known or suspectedof having poor bioavailability. It is believed that such increase canrise from one or all of the following mechanisms:

1. reducing the thickness and/or the viscosity of the mucus layer whichis present adjacent to the gastrointestinal mucosa;

2. alteration of the tight junctions between cells, thus promotingabsorption through the paracellular route;

3. inducing a change in the cell membrane structure, thus promotingtranscellular absorption;

4.increasing the hydrophobic environment within the cellular membrane.

The present dosage forms include an amount of effervescent agenteffective to aid in penetration of the drug in the gastrointestinaltract. The amount of effervescent employed must not merely permit rapiddispersion of the medicament in the gastrointestinal tract, but must aidin penetration of the drug across the gastrointestinal mucosa. Theformulations of the present invention may be distinguished from othereffervescent formulation that are enteric coated on the basis of theamount of effervescent material that they contain. Prior formulationscontain approximately half to a quarter as much bicarbonate as drug on aweight basis (together with a proportionate amount of acid). In thesecases, the small amount of effervescent couple serves only to rapidlydisintegrate the tablet.

The dosage forms of the present invention should preferably contain atleast twice as much sodium bicarbonate (or an equivalent amount of otherbase) as drug (on a weight basis) together with the proportionate amountof an appropriate acid for generating the effervescent reaction. Morepreferably the present dosage forms should contain at least three timesas much sodium bicarbonate as drug (on a weight basis) together with theproportionate amount of an appropriate acid. These high concentrationsof effervescent couple are needed to generate effervescence insufficient amounts to promote permeability and absorption of the drug.

Preferably, the effervescent is provided in an amount of between about5% and about 95% by weight, based on the weight of the finished tablet,and more preferably in an amount of between about 30% to about 60%.However, the amount of effervescent agent must be optimized for eachspecific drug.

The term “effervescent penetration enhancer” includes compounds whichevolve gas. The preferred effervescent penetration enhancers evolve gasby means of a chemical reaction which takes place upon exposure of theeffervescent penetration enhancer to water and other fluids. Suchwater-activated materials must be kept in a generally anhydrous stateand with little or no absorbed moisture or in a stable hydrated form,since exposure to water will prematurely disintegrate the tablet. Theacid sources may be any which are safe for human consumption and maygenerally include food acids, acid and hydrite antacids such as, forexample, citric, tartaric, amalic, fumeric, adipic, and succinics.Carbonate sources include dry solid carbonate and bicarbonate salt suchas, preferably, sodium bicarbonate, sodium carbonate, potassiumbicarbonate and potassium carbonate, magnesium carbonate and the like.

The effervescent penetration enhancers of the present invention is notlimited to those which are based upon a reaction which forms carbondioxide. Reactants which evolve oxygen or other gases and which are safefor human consumption are also considered within the scope of thepresent invention.

The present dosage forms may also include in amounts additional to thatrequired for effervescence a pH adjusting substance. For drugs that areweekly acidic or weakly basic, the pH of the aqueous environment caninfluence the relative concentrations of the ionized and the unionizedforms of the drug present in solution, according to theHenderson-Hasselbach equation. Th pH of solutions in which aneffervescent couple with equimolar amounts of base and acid hasdissolved is slightly acidic due to the evolution of CO₂. While it isimpractical and may not be desirable to change the pH of the contents ofthe small intestine, it is, nevertheless, possible to alter the pH ofthe local environment (intestinal contents in immediate contact with thetablet and any drug that may have dissolved from it). This is achievedby incorporating in the tablet certain pH adjusting substances. Thus,the relative proportions of the ionized and unionized forms of the drugmay be controlled.

In this way the system can be optimized for each specific drug underconsideration: if the drug is known, or suspected, to be absorbedthrough the cell membrane (transcellular absorption), it would be mostappropriate to alter the pH of the local environment to a level thatfavors the unionized form of the drug. Conversely, if the ionized formis more readily dissolved the local environment should favor ionization.Thus, for fentanyl, as a nonlimiting example, the pH is adjusted toneutral (or slightly higher) since the pKa is 7.3. At this pH, theaqueous solubility of this poorly water-soluble drug is not compromisedunduly, yet allowing a sufficient concentration of the drug to bepresent in the unionized form. This facilitates the permeationenhancement brought about by effervescence. In the case ofprochlorperazine (pKa=8.1), a slightly higher pH is required.

Suitable pH adjusting substance for use in the present invention includeany weak acid or weak base (in amounts additional to that required foreffervescence) or, preferably, any buffer system that is not harmful tothe gastrointestinal mucosa. These include, but are not limited to, anyof the acids or bases previously mentioned as the effervescentcomponents, sodium carbonate, potassium carbonate, potassium carbonate,disodium hydrogen phosphate, sodium dihydrogen phosphate, and theequivalent potassium salts.

The active agents suitable for use in the present invention preferablyincludes any drug that displays poor bioavailability, slow absorption orlong t_(max). These active ingredients include small molecule drugs,nutritional supplements (such as vitamins and minerals), proteins andpeptides and other substances of biological origin. Examples of suchdrugs include, but are not limited to, the following:

Drug Bioavailability (%) Acyclovir 15-30 Auranofin 15-25 Bretylium 23 ±9  Cyclosporine 23 ± 7  Cytarabine 20 Doxepin 27 ± 10 Doxorubicin  5Hydralazine 16-35 Ketamine 20 ± 7  Labetalol 18 ± 5  Mercaptopurine 12 ±7  Methyldopa 25 ± 16 Nalbuphine 25 ± 16 Naloxone  2 Pentoxifylline 19 ±13 Pyridostigmine 14 ± 3  Terbutaline 14 ± 2  Verapamil 22 ± 8 Riboflavin 11 Atenolol 50

Pharmaceutical ingredients suitable for use in the present dosage formsmay include, without limitation, analgesics, anti-inflammatories,antipyretics, antibiotics, antimicrobials, laxatives, anorexics,antihistamines, antiasthmatics, antidiuretics, antiflatuents,antimigraine agents, antispasmodics, sedatives, antihyperactives,antihypertensives, tranquilizers, decongestants, beta blockers;peptides, proteins, oligonucleotides and other substances of biologicalorigin, and combinations thereof. Also encompassed by the terms “activeingredient(s)”, “pharmaceutical ingredient(s)” and “active agents” arethe drugs and pharmaceutically active ingredients described in Mantelle,U.S. Pat. No. 5,234,957, in columns 18 through 21. That text of Mantelleis hereby incorporated by reference. Alternatively or additionally, theactive ingredient can include drugs and other pharmaceuticalingredients, vitamins, minerals and dietary supplements as the same aredefined in U.S. Pat. No. 5,178,878, the disclosure of which is alsoincorporated by reference herein.

The dosage forms preferably contain materials that aid in releasing thedrug in a specific section of the gastrointestinal tract thus promotingsite-specific delivery. There are various mechanisms by which suchmaterials promote site-specific delivery and this invention is notlimited to any one mechanism. For example, the material may bemetabolized by enzymes present in a specific part of thegastrointestinal tract, thus releasing the drug in that section.

The materials used to promote site-specific absorption may preferably beincluded as coatings and/or as matrix materials. If a coating is used,it may be applied to the entire dosage form or to the individualparticles of which it consists. Coating materials may be used to preventthe release of the active agent before the dosage form reaches the siteof more efficient absorption.

The coating can also be used in conjunction with an effervescence tocause the effervescence to occur at specific areas of thegastrointestinal tract. Nonlimiting examples or coatings used in thepresent invention include: cellulose derivatives including celluloseacetate phthalate (CAP); shellac and certain materials sold under thetrademark Eudragit™ (various grades may be used in specificcombinations). Hydroxypropylmethyl cellulose phthallate in a grade thatdissolves at pH 5 is the preferred coating material.

Precoating materials may also be used in the present invention.Nonlimiting examples include cellulose derivatives such asmethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcelluloseor combinations and certain materials sold under the trademark Eudragit™(various grades which may be combined). Hydroxypropylmethyl cellulosephthallate in a grade that dissolves at pH 5 is the preferred coatingmaterial.

Other materials may be used to aid in site specific delivery, andinclude, for example, sugars, polysaccharides, starches, polymers, etc.These compounds may be included as coatings or as matrix materials andaid in releasing the drug in specific sections of the gastrointestinaltract, thus promoting site-specific delivery.

Other ingredients or techniques may preferably be used with the presentdosage forms to enhance the absorption of the pharmaceutical ingredient,to improve the disintegration profile, and/or to improve theorganoleptic properties of the material and the like. These include, butare not limited to, the use of additional chemical penetrationenhancers, which are referred to herein as noneffervescent penetrationenhancers; absorption of the drug onto fine particles to promoteabsorption by specialized cells within the gastrointestinal tract (suchas the M cells of Peyer's patches); ion pairing or complexation; and theuse of lipid and/or surfactant drug carriers. The selected enhancementtechnique is preferably related to the route of drug absorption, i.e.,paracellular or transcellular.

A bioadhesive polymer may preferably be included in the drug deliverydevice to increase the contact time between the dosage form and themucosa of the most efficiently absorbing section of the gastrointestinaltract. See Jonathan D. Eichman, “Mechanastic Studies onEffervescent-Induced Permeability Enhancement,” University ofWisconsin-Madison (1997), hereby incorporated by reference. Nonlimitingexamples of known bioadhesives used in the present invention include:carbopol (various grades), sodium carboxy methylcellulose,methylcellulose, polycarbophil (Noveon AA-1), hydroxypropylmethylcellulose, hydroxypropyl cellulose, sodium alginate, and sodiumhyaluronate.

Disintegration agents may also be employed to aid in ispersion of thedrug in the gastrointestinal tract. Disintegration agents include anypharmaceutically acceptable effervescent agent. In addition to theeffervescence-producing disintegration agents, a dosage form accordingto the present invention may include suitable noneffervescentdisintegration agents. Nonlimiting examples of disintegration agentsinclude: microcrystalline cellulose, croscarmelose sodium, crospovidone,starches and modified starches.

Apart from the effervescent material within the tablet, some additionaleffervescent components or, alternatively, only sodium bicarbonate (orother alkaline substance) may be present in the coating around thedosage form. The purpose of the latter effervescent/alkaline material isto react within the stomach contents and promote faster stomachemptying.

The drug delivery device may be in the form of a tablet, granules,pellets or other multiparticulates, capsules that can contain the drugin the form of minitablets, beads, or a powder, or any other suitabledosage form.

If tablets are used, they may be matrix tablets; layered tablets inwhich the various components are separated in different layers tooptimize their benefits; or other specialized forms of tablets,including nonconventional shapes and geometric arrangements. One exampleof a nonconventional shape is a flat-faced tablet with a biconcavecentral zone, as depicted in FIG. 1. The outer, thicker part of thetablet may contain the mucoadhesive material while the inner, thinnersegment may contain the drug and effervescent components. Thisarrangement allows drug release to a segment of the gastrointestinalmucosa in close proximity to the point at which the tablet is attachedto the mucosa.

The drug and/or the effervescent material could be present in asustained release matrix. The whole tablet may consist of this matrix orthe matrix may be confined to one, or more, layers of a multilayeredtablet. FIG. 2 depicts a multilayered tablet with a central layercontaining the drug and optional effervescent material; and twomucoadhesive layers. The tablet would adhere to the mucosa irrespectiveof its spatial orientation within the intestine.

FIGS. 3 and 4 depict the effervescent layer external to the mucoadhesivelayer of each dosage form. FIG. 3 depicts a multilayered tablet in whicha central core is completely surrounded by each subsequent layer. Such atablet may be prepared by a compression coating technique. A similarphysical arrangement of layers can also be achieved in a spheroid orpellet which may be prepared by extrusion and spheronization, layering,coating or any combination of these techniques. (See FIG. 4.) Theeffervescence will cause a thinning of the mucus layer from thegastrointestinal segment, thus facilitating adhesive of the dosage formto the cellular surface rather than to the mucus layer. This arrangementpromotes better absorption of the drug.

Tablets can be manufactured by wet granulation, dry granulation, directcompression or any other tablet manufacturing technique. The tablet maybe a layered tablet consisting of a layer of the active ingredients setforth above in layers of diverse compositions. In accordance with thepresent invention, the tablet size is preferably up to about ¾′. Inaccordance with the present invention, the multiparticulate size ispreferably up to about 3 mm. In accordance with the present invention,the tablet hardness is preferably between about 5N and 100N.

Excipient fillers can be used in connection with the present inventionto facilitate tableting. Nonlimiting examples of fillers include:mannitol, dextrose, lactose, sucrose, and calcium carbonate.

Pellets or other multiparticulates may be manufactured by granulation,layering techniques, extrusion and spheronization or other pelletmanufacturing methods. The multiparticulates are then coated with anenteric coating material as described for tablets. The coating ispreferably done in a fluid bed coater. The preferred, but nonlimiting,coating material is hydroxypropylmethyl cellulose in a grade thatdissolves at pH 5. The multiparticulates are then packed into capsules.

The granules may be made by a wet granulation process or a drygranulation process. When wet granulation is used, isopropyl alcohol,ethyl alcohol or other nonaqueous granulating agent is used. Lowmoisture content grades of these organic solvents are used.

Dry granulation may be achieved through slugging or chilsonation.Layering may be done in a fluid bed apparatus or coating pan. Nonaqueousbinders are used to aid the adherence of the added material (drug,effervescent penetration enhancer and excipients) to the startingmaterial. Nonlimiting examples of the starting material or cores arenonpareils (sucrose) or microcrystalline cellulose seeds.

The preferred technique for the manufacture of multiparticulates isextrusion and spheronization. The beads contain the drug, effervescentcouple (as previously described), a fine particle diluent which alsoaids in the formation of the beads (examples are lactose and mannitol)and a spheronization aid such as microcrystalline cellulose. Thepreferred grade of the latter is Avicel RC 591 which contains sodiumcarboxymethyl cellulose as an additional ingredient. For thisformulation, a nonaqueous solvent is used. Nonlimiting examples ofnonaqueous solvents are isopropanol and ethanol. Low moisture contentgrades are used.

The alternate (and preferred) formulation is to manufacture twopopulations of beads, one containing the acid component and the otherthe alkaline component of the effervescent couple. Each population ofbeads contains similar drug concentrations and can be manufactured usingwater. Care should be taken to ensure that each population of beads hasa similar size range and a similar density. Equal densities may beachieved by the incorporation of a nontoxic material of high density tothe population of beads that would, otherwise, have had a lower density.A nonlimiting example of such a material is barium sulfate. Equivalenceof size and density facilitates the achievement of similar emptyingrates of the beads from the stomach once the dosage forms are consumedby the subject. When the beads come into contact with the intestinalfluids, the coating dissolves and the close proximity of the beads toeach other allows the effervescent reaction to occur in situ.

The coating applied to the dosage forms of the present invention must beperformed with precision to avoid pinhole faults since water penetrationthrough such faults leads to rapid and premature disintegration of thetablet. Such coating can be performed by one skilled in the art who,additionally, takes precautions to limit abrasion and chipping of thepartially formed coat during the coating process. A fluid bed coater,pan coater or other coating apparatus may preferably be used.

The invention will be further described by reference to the followingdetailed examples. These examples are provided for the purposes ofillustration only, and are not intended to be limiting unless otherwisespecified.

INGREDIENTS mg/TABLET Riboflavin, USP 5 Silicified MicrocrystallineCellulose 19.7 Sodium Bicarbonate 18.2 Citric Acid, Anhydrous 13Crospovidone 3 Magnesium Stearate 0.9 Colloidal Silicon Dioxide 0.5TOTAL 60

The tablets were compressed to a hardness of 50 N using {fraction(3/16)} inch concave punches. The tablets had a friability of less than0.25%. Coating solution was prepared according to the following formula:

INGREDIENTS WEIGHT (gm) Hydroxypropylmethyl cellulose 418.5 phthallateTriethylcitrate 31.5 Ethanol 2025.0 Acetone 2025.0 TOTAL 4500.0

Using a fluidized bed coater, the tablets were coated to a 15% weightgain. Care was taken to fluidize the bed sufficiently so thatagglomeration of the tablets did not occur during coating but excessivemovement was avoided to minimize chipping of the tablets or abrasion ofthe coating material.

INGREDIENTS mg/PER TABLET Atenolol 7.143 Sodium bicarbonate 15.000Citric acid 10.714 Silicified microcrystalline 26.043 celluloseMagnesium stearate 0.900 Silicon dioxide 0.200 TOTAL 60.000

The tablets were compressed using {fraction (3/16)} inch concave punchesto a hardness of 40 N. The tablets were coated with hydroxypropylmethylcellulose phthallate solution as described above to a weight gain of15%. Seven tablets were packed into a size 0 elongated capsule to formthe final dosage form.

INGREDIENTS mg PER CAPSULE Atenolol 25 Sodium bicarbonate 150 Lactose 37Avicel RC 591 38 Water Qs TOTAL 250

The dry powders were blended together. Water was slowly added withmixing until a wet mass that was plastic (but not tacky) was formed. Thewet mass was passed through an extruder. The extruded material wasspheronized for 3 minutes. The beads that were formed were air dried forone hour and then dried in an oven at 35° C. overnight. The beads weresieved to remove large particles and fines.

INGREDIENTS mg PER CAPSULE Atenolol 25 Citric acid 107 Lactose 80 AvicelRC 591 38 Water Qs TOTAL 250

Population 2 was made in a similar fashion to population 1. Eachpopulation of beads was separately coated to a 20% weight gain in afluidized bed coater using the previously described coating solution.Two hundred and fifty milligrams of each population of beads was filledinto size 0 elongated capsules and this formed the final dosage form.

Various modifications of the invention described herein will becomeapparent to those skilled in the art. Such modifications are intended tofall within the scope of the appending claims.

What is claimed is:
 1. A dosage form for delivery of a therapeuticallyeffective amount of a drug to a target area in the gastrointestinaltract of a mammal; comprising: (a) a therapeutically effective amount ofa drug; (b) at least one effervescent penetration enhancer; wherein saidat least one effervescent penetration enhancer is present in an amountsufficient to increase the penetration of said drug across said targetarea of said gastrointestinal tract to permit delivery of atherapeutically effective amount of said drug; and (c) an entericcoating maintained over said drug and said at least one effervescentpenetration enhancer; wherein said enteric coating prevents the releaseof said drug and said at least one effervescent penetration enhanceruntil a time at which said dosage form reaches said target area in saidgastrointestinal tract.
 2. The dosage form of claim 1, furthercomprising at least one noneffervescent penetration enhancer.
 3. Thedosage form of claim 1, further comprising at least one disintegrationagent, wherein said disintegration agent causes the rapid dispersion ofsaid drug to said target area of said gastrointestinal tract.
 4. Thedosage form of claim 1, wherein said enteric coating comprises amaterial that reacts with an enzyme present in said target area of thegastrointestinal tract to release said drug and said effervescentpenetration enhancer.
 5. The dosage form of claim 1, wherein said dosageform is a tablet.
 6. The dosage from of claim 5 wherein said tabletcontains a biconcave zone central to two outer zones; wherein said drugand said effervescent penetration enhancer are located in said biconcavezone.
 7. The dosage form of claim 1, wherein said two outer zonescontain a bioadhesive.
 8. The dosage form of claim 1, wherein saideffervescent penetration enhancer comprises a pharmaceuticallyacceptable effervescent couple; said effervescent couple comprising anacid or equivalent thereof and a base or equivalent thereof.
 9. Thedosage form of claim 8 wherein said base is sodium bicarbonate.
 10. Thedosage form of claim 1 wherein said drug is a drug that displays poorbioavailability in said gastrointestinal tract.
 11. The dosage form ofclaim 1, wherein said effervescent penetration enhancer comprises apharmaceutically acceptable effervescent couple comprising an acid and abase, wherein said acid is selected from the group consisting of citric,tartaric, amalic, fumeric, adipic, and succinic acids, and said base isselected from the group consisting of sodium bicarbonate, sodiumcarbonate, potassium bicarbonate, potassium carbonate and magnesiumcarbonate.
 12. The dosage form of claim 2, further comprising anoneffervescent disintegration agent.
 13. The dosage form of claim 2,wherein said protective coating comprises a material that reacts with anenzyme present in said area of the gastrointestinal tract to releasesaid drug, said effervescent penetration enhancer and saidnoneffervescent penetration enhancer.